Design, Synthesis, and Biological Activity of Peptides which Release Growth Hormone in Vitro*

Momany, Frank A.; Bowers, Cyril Y.; Reynolds, G. A.; Chang, Ding; Hong, Anita; Newlander, Kenneth A.

doi:10.1210/endo-108-1-31

Cited by 199 publications

(94 citation statements)

References 11 publications

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“…GHSs stimulate GH release from the pituitary somatotropes by acting on receptors different from those for GHRH (Momany et al, 1981). In the mid-1990s, the GHS-receptor (GHS-R), a G-protein-coupled seventransmembrane receptor was first detected in the anterior pituitary and hypothalamus of rats and humans (Pong et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Bhatti

Duchateau

Ham

et al. 2006

The Veterinary Journal

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The effects of three growth hormone secretagogues (GHSs), ghrelin, growth hormone-releasing peptide-6 (GHRP-6), and growth hormone-releasing hormone (GHRH), on the release of adenohypophyseal hormones, growth hormone (GH), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinising hormone (LH), prolactin (PRL) and on cortisol were investigated in young and old healthy Beagle dogs.Ghrelin proved to be the most potent GHS in young dogs, whereas in old dogs GHRH administration was associated with the highest plasma GH concentrations. The mean plasma GH response after administration of ghrelin was significantly lower in the old dogs compared with the young dogs. The mean plasma GH concentration after GHRH and GHRP-6 administration was lower in the old dogs compared with the young dogs, but this difference did not reach statistical significance. In both age groups, the GHSs were specific for GH release as they did not cause significant elevations in the plasma concentrations of ACTH, cortisol, TSH, LH, and PRL. It is concluded that in young dogs, ghrelin is a more powerful stimulator of GH release than either GHRH or GHRP-6. Ageing is associated with a decrease in GH-releasing capacity of ghrelin, whereas this decline is considerably lower for GHRH or GHRP-6.

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Section: Introductionmentioning

confidence: 99%

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Bhatti

Duchateau

Ham

et al. 2006

The Veterinary Journal

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“…The growing family of synthetic growth hormone (GH) secretagogues (GHSs) (Camanni et al 1998) consists of peptides and non-peptides structurally derived from metenkephalin and synthesized by Bowers and collaborators in the early 1980s (Momany et al 1981, Bowers 1998. Since the peptidyl GHSs have very low oral bioavailability and short half-lives, several small non-peptidyl molecules have been designed which are less susceptible to degradation and have higher bioavailability.…”

Section: Introductionmentioning

confidence: 99%

Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation

Pettersson

Muccioli²,

Granata³

et al. 2002

Journal of Endocrinology

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Recent experimental data demonstrate cardiovascular effects of the GH secretagogues (GHSs) hexarelin and ghrelin, the proposed natural ligand for the GHS receptor. Moreover, specific cardiac binding sites for GHSs have been suggested. The aim of the present study was to investigate if the natural ligand ghrelin and synthetic GHS peptide hexarelin and analogues have direct effects on the cardiomyocyte cell line, H9c2. Hexarelin stimulated thymidine incorporation in a dose-dependent manner with significant responses at 3 µM (147 3% of control, P<0·01) and elicited maximal effects at concentrations around 30 µM. This activity was seen already after 12 h of incubation with a maximal effect after 18 h (176 9% of control, P<0·01). Ghrelin also had a significant stimulatory effect on thymidine incorporation (129 2% of control at 3 µM and 18 h, P<0·05). The stimulatory effect on thymidine incorporation of hexarelin, Tyr-Ala-hexarelin, EP80317 and ghrelin was specific and no stimulatory effect was observed with the truncated GH-releasing peptide EP51389 or the non-peptidyl GHS MK-0677. In competitive binding studies, 125 I-labeled Tyr-Alahexarelin was used as radioligand and competition curves showed displacement with hexarelin, Tyr-Ala-hexarelin, EP80317 and ghrelin, whereas MK-0677 and EP51389 produced very little displacement at 1 µM concentration, adding further support for an alternative subtype binding site in the heart compared with the pituitary. In conclusion, we have demonstrated a dose-dependent and specific stimulation of cardiomyocyte thymidine incorporation by natural and synthetic GHS analogues, suggesting increased cell proliferation and binding of GHS to H9c2 cardiomyocyte cell membranes. These findings support potential peripheral effects of GHS on the cardiovascular system independent of an increased GH secretion.

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“…We elucidated the mechanism of action of a class of small, synthetic, GH-releasing peptides, and used this knowledge to develop nonpeptide mimetics (2)(3)(4)(5). The mimetic MK-0677, when administered chronically to elderly subjects, resulted in sustained rejuvenation of the physiological profile of the growth hormone axis, and increased lean but not fat mass in obese subjects (6,7).…”

mentioning

confidence: 99%

Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor

Sun

Wang

Zheng

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

661

530

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Synthetic agonists of the growth hormone secretagogue receptor (GHSR) rejuvenate the pulsatile pattern of GH-release in the elderly, and increase lean but not fat mass in obese subjects. Screening of tissue extracts in a cell line engineered to overexpress the GHSR led to the identification of a natural agonist called ghrelin. Paradoxically, this hormone was linked to obesity. However, it had not been directly shown that the GHSR is a physiologically relevant ghrelin receptor. Furthermore, ghrelin's structure is significantly different from the synthetic agonist (MK-0677) used to expression-clone the GHSR. To address whether the GHSR mediates ghrelin's stimulatory effects on GH release and appetite, we generated Ghsr-null mice. In contrast to wild-type mice, acute treatment of Ghsr-null mice with ghrelin stimulated neither GH release nor food intake, showing that the GHSR is a biologically relevant ghrelin receptor. Nevertheless, Ghsr-null mice are not dwarfs; their appetite and body composition are comparable to that of wild-type littermates. Furthermore, in contrast to suggestions that ghrelin regulates leptin and insulin secretion, fastinginduced changes in serum levels of leptin and insulin are identical in wild-type and null mice. Serum insulin-like growth factor 1 levels and body weights of mature Ghsr-null mice are modestly reduced compared to wild-type littermates, which is consistent with ghrelin's property as an amplifier of GH pulsatility and its speculated role in establishing an insulin-like growth factor 1 set-point for maintaining anabolic metabolism. Our results suggest that chronic treatment with ghrelin antagonists will have little effect on growth or appetite.

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Design, Synthesis, and Biological Activity of Peptides which Release Growth Hormone in Vitro*

Cited by 199 publications

References 11 publications

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation

Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor

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